External preparation of 2-amino-2-(2-(4-octylphenyl)ethyl) propane-1,3-diol or pharmaceutically acceptable salts thereof for topical administration

ABSTRACT

An external preparation for topical administration which aims at inhibiting rejection reactions at organ or bone marrow transplantation or treating autoimmune diseases or allergic diseases and contains as the active ingredient 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof.

This application is a division of application Ser. No. 08/894,728, filedAug. 27, 1997, which is a 371 of PCT/JP96/03757 Dec. 24, 1996.

TECHNICAL FIELD

This invention relates to an external preparation for topicaladministration, in more detail to an external preparation for topicaladministration which contains as the active ingredient2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or pharmaceuticallyacceptable acid-addition salts thereof.

1. Background Art

WO94/08943 discloses 2-aminopropane-1,3-diol compounds which are usefulas immunosuppressive agents. Among those compounds,2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hydrochloride(hereunder sometimes referred to as Compound (I)) is under research anddevelopment for the transplantation of organs and autoimmune diseases.In order to inhibit rejection reaction at organs or bone marrow andtreat autoimmune diseases and allergic diseases, drugs are usuallyapplied topically to the affected parts in addition to the oraladministration. Then, it has been desirable to develop thepharmaceutical preparations of Compound (I) which can be administeredthrough the skin, eye, lung, bronchus, nose or rectum.

2. Disclosure of the Invention

From the point of view as above, the present inventors have madeintensive investigations for the development of a pharmaceuticalpreparation of Compound (I) which can be administered through the skin,eye, lung, bronchus, nose or rectum, and have succeeded in formulatingsuch pharmaceutical preparation and thereby completed the presentinvention.

Namely, the present invention relates to an external preparation fortopical administration which contains as the active ingredient2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or pharmaceuticallyacceptable acid-addition salts thereof (hereunder sometimes referred toas the compound of the present invention).

The compound of the present invention may be prepared in accordance withthe methods described in WO94/08943.

The pharmaceutically acceptable acid-addition salts are inclusive of asalt with an inorganic acid such as hydrochloride, hydrobromide orsulfate, or a salt with an organic acid such as acetate, fumarate,maleate, benzoate, citrate, malate, methanesulfonate orbenzenesulfonate, preferably hydrochloride. The present inventionembraces the hydrate or solvate of the compound of the presentinvention.

The external preparation for topical administration which is applicableto the compound of the present invention includes an ointment, a paste,a liniment, a lotion, a plaster, a cataplasm, an eye drop, an eyeointment, a suppository, a fomentation, an inhalant, a spray, anaerosol, a paint, a nasal drop, a cream, a tape, a patch and the like.

The external preparation for topical administration of the presentinvention contains the compound of the present invention in a form of amixture with an organic or inorganic carrier or excipient, and, forexample, can be used in a form a solid, semi-solid or solutionpharmaceutical preparation.

The compound of the present invention can be mixed with, for example, anon-toxic and pharmaceutically acceptable carrier which is usuallyemployed for obtaining an external preparation for topicaladministration.

A carrier which can be used includes water, glucose, lactose, arabicgum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, cornstarch, keratin, colloid silica, potato starch, urea and other carrierswhich are suitable for preparing a solid, semi-solid or solutioncomposition. Further, an adjuvant, a stabilizer, a thickener, a coloringmatter or a flavoring agent can be added.

The compound of the present invention as an active ingredient of theexternal preparation for topical administration of the present inventioncan be contained in an amount enough to exhibit the desired activitydepending on the symptom or severity of the diseases. In the case of thetreatment of the symptom and diseases induced from immune disorder asmentioned below, the compound of the present invention can beadministered by way of a topical administration, an aerosol or a rectaladministration in a form of a dosage unit composition which containspharmaceutically acceptable and non-toxic carrier, adjuvant andexcipient. In the treatment of reversible obstructive airways disease,the compound of the present invention is preferably administered to lungby an aerosol in a form of, particularly a powder or a solution.

The amount of the compound of the present invention which can be mixedwith a carrier can vary depending on the host to be treated and aspecified dosage form. The specified dose of the specified patientshould be determined depending on the various factors such as age, bodyweight, the whole condition of health, sex, meal, time foradministration, administration route, rate of excretion, combination ofdrug and the severity of the specified diseases under treatment.

The external preparation for topical administration containing thecompound of the present invention will be explained in more detail asfollows:

When the compound of the present invention is used in the form of anointment, it is contained in an amount of 0.01 to 10 w/w % in theointment.

The ointment base which can be used includes oleaginous base (a naturalwax such as white beeswax or carnauba wax, a petroleum wax such as solidparaffin or microcrystalline wax, a hydrocarbon wax such as liquidparaffin, white soft paraffin or yellow petrolatum, plastibase, zelen50W, silicone, a vegetable oil, pork tallow, beef tallow, a simpleointment or lead oleate plaster), an emulsion type ointment base (an O/Wtype base such as a hydrophilic ointment or a vanishing cream or a W/Otype base such as a hydrophilic petrolatum, a purified lanolin,aquahole, eucelin, neocelin, an absorptive ointment, a hydrated lanolin,cold cream, a hydrophilic plastibase), a water-soluble base (a macrogolointment or solbase) or a suspension type ointment base (a lyogel base,i.e. a hydrogel base such as a non-fat ointment, a gelbase or lotion; oran FAPG base (a suspension of a microparticle of an aliphatic alcoholsuch as stearyl alcohol or cetyl alcohol in propylene glycol), and theseointment base can be used alone or in a combination of not less than twobases.

Further, when to be used as an ointment, the compound of the presentinvention is dissolved in a solubilizing and absoptive acceleratingagent and added to the above-mentioned ointment base.

The solubilizing and absoptive accelerating agent to be used means theagent in which the compound of the present invention is soluble at aconcentration of at least not less than 0.01 w/w % and which canaccelerate the absorption of the compound of the present invention fromskin when formulated as an ointment, and includes a lower alkanediol(e.g. ethylene glycol, propylene glycol or butylene glycol), an alkylenecarbonate (e.g. propylene carbonate or ethylene carbonate), analkanedicarboxylic acid ester (e.g. dimethyl adipate, diethyl adipate,diisopropyl adipate, diethyl pimerate, diethyl sebacate or dipropylsebacate), a higher alkanoic acid glycerin ester (e.g. monolaurin,dilaurin or trilaurin), a higher alkenoic acid glycerin ester (e.g.monoolein, diolein or triolein), a higher alkanoic acid alkyl ester(e.g. isopropyl myristate or ethyl myristate), a higher unsaturatedalcohol (e.g. geraniol or oleyl alcohol) or an azacycloalkane (e.g.1-dodecylazacycloheptan-2-one). These solubilizing and absoptiveaccelerating agent can be used alone or in a mixture of not less thantwo agents, and can be added at a sufficient amount to dissolve thecompound of the present invention. The amount generally ranges from 2parts by weight to 200 parts by weight per one part by weight of thecompound of the present invention. The upper amount is limited not todeteriorate the physicochemical properties of the ointment.

The ointment which contains the compound of the present invention maycontain, in addition to the above-mentioned ointment base, otheradditives such as an emulsifier (e.g. polyoxyethylene hardened casteroil, glycerol monostearate, sorbitan sesquioleate or lauromacrogol); asuspending agent (e.g. polyoxyethylene glycol, polyvinylpyrrolidone orsodium carboxymethylcellulose); an antioxidant (e.g. a phenol or aquinone; a preservative (e.g. paraoxybenzoic acid ester); a humectant(e.g. glycerin, D-sorbitol or propylene glycol); a favoring agent, acoloring matter; an antiseptic; a higher alkenoic acid (e.g. oleicacid), and moreover other drugs which are useful for the treatment of askin diseases.

The ointment of the present invention can be prepared by mixing asolution containing the compound of the present invention with anointment base in accordance with a conventional method. In the processof formulation, not less than one of the adjuvant or additive mentionedabove can be simultaneously added to the ointment base. Furthermore, theointment can be manufactured by dissolving the compound of the presentinvention in the solubilizing and absoptive accelerating agent, admixingthe obtained solution with the ointment base, stirring the obtainedmixture under heating, and then cooling the resultant mixture.

The ointment containing the compound of the present invention can beused by applying to the affected part of the skin once to several times(e.g. once to four times) a day.

The paste or liniment containing the compound of the present inventioncan be prepared by using the same base and according to the same methodas those of the ointment as mentioned above.

The lotion containing the compound of the present invention means aminute and homogeneous suspension or partial solution of the activeingredient compound in a liquid medium, and an emulsifier can be addedthereto.

In case that the compound of the present invention is used as a lotion,the content may be adjusted to 0.01 to 10 w/w % in the lotion.

The liquid medium to be used in the lotion containing the compound ofthe present invention includes water, a lower alcohol, a glycol,glycerin or a mixture thereof. Among them, all of the lower alcoholswhich do not decompose the active ingredient and are not irritant toskin can be used, and are inclusive methanol, ethanol, isopropylalcohol, propanol or butanol. The glycol includes ethylene glycol,propylene glycol, butylene glycol or mono lower ethers thereof. Amongthese liquid media, water, the lower alcohol or a mixture thereof aremost preferable because these media improve the absorption of the activeingredient to the skin. The amount of these liquid media preferablyranges from 5 parts by weight to 1,000 parts by weight per one part byweight of the compound of the present invention.

Further, to the lotion containing the compound of the present inventionmay be added a solubilizing and absoptive accelerating agent in whichthe compound of the present invention is soluble at a concentration ofat least not less than 0.01 w/w % and which can accelerate theabsorption of the compound of the present invention from skin whenformulated as a lotion, and includes an alkanedicarboxylic acid ester(e.g. dimethyl adipate, diethyl adipate, diisopropyl adipate, diethylpimerate, diethyl sebacate or dipropyl sebacate) or a higher alkanoicacid alkyl ester (e.g. isopropyl myristate or ethyl myristate).

These solubilizing and absoptive accelerating agent can be used alone orin a mixture of not less than two agents. The amount generally rangesfrom 5 parts by weights to 5,000 parts by weights per one part by weightof the compound of the present invention. The content of thesolubilizing and absoptive accelerating agent is desirably in the rangeof 1 to 30 w/w %.

The emulsifier for the lotion containing the compound of the presentinvention is employed for the purpose of suspending an insolublemedicine minutely and homogeneously in an aqueous solution, and shouldbe non-toxic to human beings, and includes a pharmaceutically acceptablenatural emulsifier and synthetic emulsifier.

Various emulsifiers which are derived from animals and vegetables can beused as the natural emulsifier, and include egg lecithin, soybeanlecithin or a hydrogenated product thereof, phosphatidyl choline,sphingomyelin, arabic gum or gelatin. Cationic, anionic or non-ionicsurfactants can be used as the synthetic emulsifier, and preferablyinclude a castor oil surfactant, especially an HCO (polyoxyethylenehardened castor oil) such as HCO-60, HCO-50 or HCO-40. Further, apolyoxyethylenesorbitan aliphatic acid ester such as polysorbate 80, aglycerin aliphatic acid ester such as glycerin monocaprylate, apolyoxyethylene aliphatic acid ester such as polyoxyethylene 40monostearate, a middle chain aliphatic acid mono(or di)glyceride (e.g.C₆-C₁₂ aliphatic acid mono(or di)glycerides such as caprylic aciddiglyceride, caprylic acid monoglyceride or caproic acid diglyceride) ora polyoxyethylated glyceride such as polyoxyethylated oleic acidglyceride.

The above-mentioned emulsifiers can be used as the primary emulsifier,and, if necessary, in combination with an auxiliary emulsifier. Theauxiliary emulsifier is conventional and non-toxic to human beings, andincludes cholesterol, agar, magnesium hydroxide, methylcellulose orpectin.

These primary emulsifier and auxiliary emulsifier may be used each aloneor in combination of two or more of them, respectively.

The emulsifier is contained in the lotion of the present invention in anamount being able to emulsify the compound of the present invention andother additives to be contained, and preferably ranges from 0.1 part byweight to 10 parts by weight per one part by weight of the compound ofthe present invention.

In order to increase the viscosity, a viscosity-increasing agent may beadded to the lotion of the present invention. The viscosity-increasingagent is any conventional agent which is usually added to give theviscosity to the liquid and is non-toxic to human beings, and includescarboxypolymethylene. The viscosity-increasing agent is used when thelotion with a high viscosity is desired. The content of theviscosity-increasing agent may vary depending on the desired viscosityof the lotion and preferably ranges from 0.01 to 5 w/w %.

The lotion of the present invention may further contain a stabilizerwhich is used for the stabilization of the active ingredient compound inan aqueous solution, and if necessary, it may further contain otheradditives which are usually used for the lotion, such as a favoringagent, a coloring matter, an antiseptic or a higher alkenoic acid suchas oleic acid, or other drugs which are useful for the treatment of theskin diseases.

The lotion which contains the compound of the present invention may beprepared by a conventional method in this field.

The lotion which contains the compound of the present invention can beused by applying to the affected part of the skin once to several times(e.g. once to four times) a day. When the lotion has a low viscosity, itcan be applied by filling the composition of the lotion to a sprayvessel and spraying directly to the skin.

In case that the compound of the present invention is used in the formof an eye drop or a nasal drop, the solvent employed includes a steriledistilled water or, in particular a distilled water for injection. Theconcentration of the active compound usually ranges from 0.01 to 2.0 w/v%, and may be increased or decreased depending on the aim of use.

The eye drop or a nasal drop which contains the compound of the presentinvention further may contain various additives such as a buffer, anisotonic agent, a solubilizing agent, a preservative, aviscosity-increasing agent, a chelating agent, a pH adjustor or anaromatic.

The buffer includes, for example, a phosphate buffer (e.g. sodiumdihydrogen phosphate-disodium hydrogen phosphate or potassium dihydrogenphosphate-dipotassium hydrogen phosphate), a borate buffer (e.g. boricacidborax), a citrate buffer (e.g. sodium citrate-sodium hydroxide), atartrate buffer (e.g. tartaric acid-sodium tartrate), an acetate buffer(e.g. acetic acid-sodium acetate), a carbonate buffer (e.g. sodiumcarbonatecitrate or sodium carbonate-boric acid) or an amino acid (e.g.sodium glutamate or ε-aminocapronic acid).

The isotonic agent includes a saccharide such as sorbitol, glucose ormannitol, a polyhydric alcohol such as glycerin or propylene glycol, asalt such as sodium chloride or borax, or boric acid and the like.

The solubilizing agent includes a non-ionic surfactant such aspolyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylenemonostearate, polyethylene glycol or polyoxyethylene hardened castor oiland the like.

The preservative includes, for example, a quaternary ammonium salt suchas benzalkonium chloride, benzethonium chloride or cetyl pyridiniumchloride, a parahydroxybenzoic acid ester such as methylparahydroxybenzoate, ethyl parahydroxybenzoate, propylparahydroxybenzoate or butyl parahydroxybenzoate, benzyl alcohol,phenethyl alcohol, sorbic acid or a salt thereof, thimerosal,chlorobutanol, sodium dehydroacetate, methylparaben or propylparaben.

The viscosity-increasing agent includes, for example,polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose,methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcelluloseor a salt thereof.

The chelating agent includes disodium edetate or citric acid and thelike.

The pH adjustor includes hydrochloric acid, citric acid, phosphoricacid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide,sodium carbonate or sodium bicarbonate and the like.

The aromatic includes 1-menthol, borneol, a camphor (e.g. d1-camphor) oreucalyptus oil and the like.

The eye drop which contains the compound of the present invention may beusually adjusted to about 4.0 to about 8.5 of pH, and the nasal drop toabout 4.0 to about 8.5 of pH.

The eye drop may contain the compound of the present invention in asufficient amount to be able to effectively prevent the eyeinflammation, which may vary depending on the symptom or the sort ofinflammation, and usually ranges from about 5.0 to about 1,000 μg forone administration. It may be administered once to several times (e.g.once to four times) a day.

The aerosol containing the compound of the present invention means apharmaceutical preparation which can be applied at the time of treatmentby spraying a solution or a suspension of the active compound using apressure of a liquid gas or compressed gas filled in the same vessel oranother vessel. The aerosol can be prepared by dissolving the compoundof the present invention in a distilled water, and, if necessary,dissolving or suspending the solution in the same solubilizing andadsorptive accelerating agent as above, and, if necessary, adding theadditive such as pH adjustor or antiseptic as mentioned above, and thensealing closely with a valve and compressing the propellant. Thepropellant to be used includes dimethyl ether, liquid natural gas,carbon dioxide, nitrogen gas, a substituted flon gas and otherconventional propellants.

The aerosol may further contain a refrigerant such as 1-menthol, acamphor, methyl salicylate and the like.

The inhalant or spray which contains the compound of the presentinvention can be prepared according to the same methods as thosementioned in aerosol. An inhaler or a nebulizer can be used for inhalantand a spraying vessel can be used for spray.

When the compound of the present invention is used as a suppository, thesuppository can be prepared in a conventional manner using aconventional base for the suppository. The compound of the presentinvention is contained in the suppository in an amount sufficient toexhibit the pharmaceutical effect, which can vary depending on the ageor symptom of the patient, and preferably ranges from 0.1 to 60 mg.

The base for suppository of the present invention is the conventionalbase, and includes an oil and fat from animal and vegetable such asolive oil, corn oil, castor oil, cotton seed oil, oil from wheat withgerm, cacao oil, beef tallow, pork tallow, wool tallow, turtle tallow,squalene or a hardened oil, an oil and fat from mineral such asVaseline, white soft paraffin, solid paraffin, liquid paraffin,dehydrated lanolin or silicon oil, a wax such as hohoba oil, carnaubawax, yellow bees wax or lanolin, or a partially synthetic or totallysynthetic glycerin aliphatic acid ester such as mono, di or triglycerideof a middle or higher aliphatic acid such as a straight-chain saturatedaliphatic acid (e.g. lauric acid, myristic acid, palmitic acid orstearic acid), or a straight-chain unsaturated aliphatic acid (e.g.oleic acid, linoleic acid or linolenic acid). The commercially availableproducts are exemplified Witepsol [manufactured by Dynamitnobel Co.; amixture of mono-, di- and triglycerides of C₁₂-C₁₈ saturated aliphaticacid, in more detail, Witepsol H series (e.g. Witepsol H5, H12, H19,H32, H35, H37, H39, H42, H175 or H185), Witepsol W series (e.g. WitepsolW25, W31, W35 or W45), Witepsol E series (e.g. Witepsol E75, E76, E79 orE85) or Witepsol S series (e.g. Witepsol S52, S55 or S58) are included);Pharmasol (manufactured by Nippon Oils and Fats Co.); Isocacao(manufactured by Kao Co.); SB (manufactured by Kanegafuchi Chemical Co.and Taiyo Yusi Co.; a mixture of mono-, di- and tri-glycerides ofC₁₂-C₁₈ saturated aliphatic acid, in more detail, SB-H, SB-E or SB-AMare included); Nopata (manufactured by Henkel AG.); Sapoyer(manufactured by Gattfords Co.; a mixture of mono-, di- andtri-glycerides of C₁₀-C₁₈ saturated aliphatic acid, in more detail,Sapoyer NA, Sapoyer OS, Sapoyer AS, Sapoyer BS, Sapoyer BM or sapoyer DMare included); Masaesthalinum (manufactured by Dynamitnobel Co.; amixture of mono-, di- and triglyceride of C₁₀-C₁₈ saturated aliphaticacid, in more detail, Masaesthalinum A, AB, B, BB, BC, BCF, C, D, E orBD and Masaasthalinum 299 are included); or Migriol 810 or Migriol 812(manufactured by Dynamitnobel Co.; a mixture of triglycerides of C₈-C₁₂saturated aliphatic acid, in more detail, one or more of them mayoptionally be incorporated when the partially synthetic or totallysynthetic glycerin aliphatic acid ester as mentioned above areincorporated). Further, other synthetic products such as polyethyleneglycol or polyoxyethylene alcohol can be exemplified. The bases are usedin an amount of 25 to 99.9% by weight based on the total weight of thesuppository.

To the suppository containing the compound of the present invention maybe added, if necessary, a preservative, a stabilizer, a surfactant, anaromatric, a pH adjustor or a purified water.

The suppository containing the compound of the present invention may bein various forms such as a rectal suppository which is solid at thenormal temperature and melts at a body temperature; an ointment orliquid enema which can be prepared by dissolving or suspending thecompound of the present invention in a liquid base; a soft capsule forthe rectal administration; or an injection for the rectaladministration.

The external preparation for topical administration of the presentinvention can be used for the prevention or treatment of various medicalindications, which have been already applied by the oral administrationof the compound of the present invention, such as immunosuppression inorgans or bone marrow transplantation, various autoimmune diseases orvarious allergy diseases. Namely, the compound of the present inventionhas pharmacological activities such as immunosuppressive activity orantimicrobial activity and therefore are useful for the prevention ortreatment of resistance to transplantation or transplantation rejectionof organs or tissues (such as heart, kidney, liver, lung, bone marrow,cornea, pancreas, intestinum tenue, limb, muscle, nervus, fatty marrow,duodenum, skin or pancreatic islet cell etc., includingxeno-transplantation), graft-versus-host diseases by bone marrowtransplantation (GvHD), autoimmune diseases such as rheumatoidarthritis, systemic lupus erythematosus, nephrotic syndrome lupus,Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type Idiabetes mellitus, type II adult onset diabetes mellitus, uveitis,nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis,palmoplantar pustulosis, allergic encephalomyelitis, glomerulonephritis,etc., and infectious diseases caused by pathogenic microorganisms.

The active compound is also useful for treating inflammatory,proliferative and hyperproliferative skin diseases and cutaneousmanifestations of immunologically-mediated illnesses such as psoriasis,psoriatic arthritis, atopic eczema (atopic dermatitis), contactdermatitis and further eczematous dermatitises, seborrheic dermatitis,lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa,urticaria, angioedemas, vasculitides, erythemas, cutaneouseosinophilias, acne, alopecia areata, eosinophilic fasciitis, andatherosclerosis.

More particularly, the compound of the present invention is useful inhair revitalizing, such as in the treatment of female or male patternalopecia, or senile alopecia, by providing epilation prevention,hair-germination, and/or a promotion of hair generation and hair growth.

The compound of the present invention is further useful in the treatmentof respiratory diseases, for example, sarcoidosis, fibroid lung,idiopathic interstitial pneumonia, and reversible obstructive airwaysdisease, including conditions such as asthma, including bronchialasthma, infantile asthma, allergic asthma, intrinsic asthma, extrinsicasthma and dust asthma, particularly chronic or inveterate asthma (forexample late asthma and airway hyperreponsiveness), bronchitis and thelike.

The compound of the present invention may also be useful for treatinghepatic injury associated with ischemia.

The compound of the present invention is also applied to certain eyediseases such as conjunctivitis, keratoconjunctivitis, keratitis, vernalconjunctivitis, uveitis associated with Behcet's disease, herpetickeratitis, conical cornea, dystorphia epithelialis corneae,keratoleukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves'ophthalmopathy, severe intraocular inflammation and the like.

The compound of the present invention is also useful for preventing ortreating inflammation of mucosa or blood vessels (such as leukotrieneB4-mediated diseases, gastric ulcers, vascular damage caused by ischemicdiseases and thrombosis, ischemic bowel disease, inflammatory boweldisease (e.g. Crohn's disease and ulcerative colitis) necrotizingenterocolitis), or intestinal lesions associated with thermal burns.

Further, the compound of the present invention is also useful fortreating or preventing renal diseases including interstitial nephritis,Goodpasture's syndrome, hemolytic uremic syndrome and diabeticnephropathy; nervous diseases selected from multiple myositis,Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrinediseases including hyperthyroidism and Basedow's disease; hematicdiseases including pure red cell aplasia, aplastic anemia, hypoplasticanemia, idiopathic thrombocytopenic purpura, autoimmune hemolyticanemia, agranulocytosis and anerythroplasia; bone diseases includingosteoporosis; respiratory diseases including sarcoidosis, fibroid lungand idiopathic interstitial pneumonia; skin diseases includingdermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergicsensitivity and cutaneous T cell lymphoma; circulatory diseasesincluding arteriosclerosis, aortitis, polyarteritis nodosa andmyocardosis; collagen disease including scleroderma, Wegener's granulomaand Sjogren' syndrome; adiposis; eosinophilic fasciitis; periodontaldisease; nephrotic syndrome; hemolytic uremic syndrome; and musculardystrophy.

Further, the compound of the present invention is indicated in thetreatment of diseases including intestinal inflammations or allergiessuch as Coeliac disease, proctitis, eosinophilic gastroenteritis,mastocytosis, Crohn's disease or ulcerative colitis; and food relatedallergic diseases which have symptomatic manifestation remote from thegastrointestinal tract, for example migraine, rhinitis and eczema.

The compound of the present invention also has liver regeneratingactivity and/or activity in promoting hypertrophy and hyperplasia ofhepatocytes. Therefore, they are useful for the treatment and preventionof hepatic diseases such as immunogenic diseases (e.g. chronicautoimmune liver diseases including autoimmune hepatitis, primarybiliary cirrhosis and sclerosing cholangitis), partial liver resection,acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis,shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis andcirrhosis.

The compound of the present invention is also indicated for use asantimicrobial agents, and thus may be used in the treatment of diseasescaused by pathogenic microorganisms and the like.

Further, the compound of the present invention can be used in theprevention or treatment of malignant rheumatoid arthritis, amyloidosis,fulminant hepatitis, Shy-Drager syndrome, pustular psoriasis, Behcet'sdisease, systemic lupus erythematosus, endocrine opthalmopathy,progressive systemic sclerosis, mixed connective tissue disease,aortitis syndrome, Wegener's gramulomatosis, active chronic hepatitis,Evans syndrome, pollinosis, idiopathic hypoparathyroidism, Addisondisease (autoimmune adrenalitis), autoimmune orchitis, autoimmuneoophoritis, cold hemagglutinin, paroxysmal cold hemoglobinuria,pernicious anemia, adult T cell leukemia, autoimmune atrophic gastritis,lupoid hepatitis, tubulointerstitial nephritis, membranous nephritis,amyotrophic lateral sclerosis, rheumatic fever, postmyocardialinfarction syndrome and sympathetic ophthalmitis.

Moreover, the compound of the present invention can be used incombination with other immunosuppressant(s), steroid(s) (prednisolone,methylprednisolone, dexamethasone, hydrocortisone and the like) ornonsteroidal anti-inflammatory agent. As the other immunosuppressant,preferred is particularly selected from azathioprine, brequinar sodium,deoxyspergualin, mizoribine, mycophenolate 2-morphorinoethyl,cyclosporin, rapamycin, tacrolimus monohydrate.

BEST MODE FOR CARRYING OUT THE INVENTION

The following pharmaceutical examples are illustrative of the presentinvention.

Pharmaceutical Preparation 1

2-Amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hydrochloride(hereunder referred to as compound (I), 1 g) was dissolved in 19 g ofhydrophilic petrolatum under heating at 60° C., and cooled with stirringto prepare an ointment containing 5% of Compound (I).

Pharmaceutical Preparation 2

Compound (I) (1 g) was mixed well with 19 g of plastibase (gelledhydrocarbon) in a mortar for about 30 minutes to prepare an ointmentcontaining 5% of Compound (I).

Pharmaceutical Preparation 3

To a melted Witepsol H15 (72.47 g) at 40° C. was added Compound (I) (30mg), and the mixture was stirred to suspend Compound (I). Thehomogeneous mixture was filled in a container at a weight of 725 mg eachto prepare a suppository containing 0.3 mg of Compound (I) in 725 mg.

Pharmaceutical Preparation 4

To a 70 ml of sterile distilled water was added 0.2 g ofpolyvinylalcohol and it is dissolved by heating at 70° C. with stirring.To the solution was suspended homogeneously 0.1 g of polyoxyethylenehardened castor oil 60, and then the mixture was cooled to roomtemperature. To the solution were added 0.2 g of Compound (I), 0.5 g ofdisodium hydrogen phosphate, 0.1 g of sodium dihydrogen phosphate, 0.8 gof sodium chloride and 0.007 g of benzethonium chloride to give asolution. To the solution was added sterile distilled water to preparean eye drop containing Compound (I) in a total volume of 100 ml.

Pharmaceutical Preparation 5

To 70 ml of sterile distilled water were added 0.4 g of Compound (I),0.2 g of sodium citrate, 0.1 g of polysorbate 80, 2.6 g of glycerin and0.007 g of benzethonium choride, and to the solution obtained was addedsterile distilled water to prepare a nasal drop containing Compound (I)in a total volume of 100 ml.

Pharmaceutical Preparation 6

To 100 mg of Compound (I) were added 1 ml of isopropyl myristate and 4ml of ethanol at room temperature to prepare a lotion containing 2% ofCompound (I).

INDUSTRIAL APPLICABILITY

The external preparation containing the compound of the presentinvention is a useful topical preparation for inhibiting the rejectionreactions at organ or bone marrow transplantation or treating theautoimmune diseases or allergic diseases.

What is claimed is:
 1. A method for treating a disease or disorderselected from transplantation rejection of organs, transplantationrejection of tissues or graft versus host diseases, in a subject,comprising administering an effective amount of a composition of2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or a pharmaceuticallyacceptable acid addition salt thereof to said subject by a nasal,pulmonary, bronchial, or rectal administration route.
 2. A method fortreating a disease or disorder selected from autoimmune diseases,inflammatory diseases, proliferative skin diseases, hyperproliferativeskin diseases, or conjunctivititis in a subject comprising administeringa therapeutically effective amount of a composition of2-amino-2-(2(4-octylphenyl)ethyl)propane-1,3-diol or a pharmaceuticallyacceptable acid addition salt thereof to said subject by a nasal,pulmonary, bronchial, or rectal administration route.
 3. A method fortreating a disease or disorder selected from respiratory diseases,allergies, hepatic injury due to ischemia, inflammation of mucosa orblood vessels, renal diseases, or diseases that are caused by pathogenicorganisms in a subject comprising administering a therapeuticallyeffective amount of a composition of2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or a pharmaceuticallyacceptable acid addition salt thereof to said subject by a nasal,pulmonary, bronchial, or rectal administration route.
 4. The methodaccording to claim 1, wherein said disease or disorder is induced fromimmune disorder, wherein said composition is administered via an aerosolor rectal administration route.
 5. The method according to claim 2,wherein said disease or disorder is induced from immune disorder,wherein said composition is administered via an aerosol or rectaladministration route.
 6. The method according to claim 3, wherein saiddisease or disorder is a reversible obstructive airway disease, whereinsaid composition is administered via an aerosol administration route inthe form of a powder or a solution.
 7. The method according to claim 1,wherein the 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or apharmaceutically acceptable acid addition salt thereof is administeredin combination with another immunosuppressant.
 8. The method accordingto claim 2, wherein the2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or a pharmaceuticallyacceptable acid addition salt thereof is administered in combinationwith another immunosuppressant.
 9. The method according to claim 3,wherein the 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or apharmaceutically acceptable acid addition salt thereof is administeredin combination with another immunosuppressant.
 10. The method accordingto claim 7, wherein the other immunosuppressant is azathioprine,brequinar sodium, deoxyspergualin, mizoribine, mycophenolate2-morpholinoethyl, cyclosporin, rapamycin, or tacrolimus monohydrate.11. The method according to claim 10, wherein the otherimmunosuppressant is mycophenolate 2-morpholinoethyl, cyclosporin, orrapamycin.
 12. The method according to claim 8, wherein the otherimmunosuppressant is azathioprine, brequinar sodium, deoxyspergualin,mizoribine, mycophenolate 2-morpholinoethyl, cyclosporin, rapamycin, ortacrolimus monohydrate.
 13. The method according to claim 12, whereinthe other immunosuppressant is mycophenolate 2-morpholinoethyl,cyclosporin, or rapamycin.
 14. The method according to claim 9, whereinthe other immunosuppressant is azathioprine, brequinar sodium,deoxyspergualin, mizoribine, mycophenolate 2-morpholinoethyl,cyclosporin, rapamycin, or tacrolimus monohydrate.
 15. The methodaccording to claim 14, wherein the other immunosuppressant ismycophenolate 2-morpholinoethyl, cyclosporin, or rapamycin.